Cancers

24 pages, 2056 KB

Open AccessReview

Luminal and Basal Subtypes Across Carcinomas: Molecular Programs Beyond Tissue of Origin

by Celia Gaona-Romero, María Emilia Domínguez-Recio, Iñaki Comino-Méndez, María Victoria Ortega-Jiménez, Rocío Lavado-Valenzuela and Emilio Alba

Cancers 2025, 17(16), 2720; https://doi.org/10.3390/cancers17162720 - 21 Aug 2025

Viewed by 485

Abstract

Carcinomas originate from polarized epithelia, displaying luminal and basal orientations with distinct biological properties. Regardless of tissue of origin, many carcinomas show luminal or basal traits that are reflected in molecular profiles and are associated with different clinical behaviors and outcomes. Traditionally, cancers [...] Read more.

Carcinomas originate from polarized epithelia, displaying luminal and basal orientations with distinct biological properties. Regardless of tissue of origin, many carcinomas show luminal or basal traits that are reflected in molecular profiles and are associated with different clinical behaviors and outcomes. Traditionally, cancers have been classified by histology and anatomical site, but accumulating evidence indicates that luminal/basal subtyping reflects shared biological programs that transcend organ boundaries. Breast cancer was the first model in which these subtypes were defined, revealing clear prognostic and therapeutic implications. Subsequent studies have identified similar subtypes in bladder, lung, prostate, pancreatic, and head and neck carcinomas, where basal phenotypes are consistently associated with aggressive disease and distinct vulnerabilities to treatment. In this review, we synthesize advances from the last decade (2010–2024) on the basal-like subtype across epithelial tumors. We summarize key studies applying luminal/basal subtyping in large cohorts of carcinomas and in single tissue tumor types. By integrating these findings, we aim to clarify the current understanding of luminal and basal subtypes in epithelial tumors and outline their potential to refine cancer classification, improve prognostic accuracy, and guide therapeutic decision-making. This perspective supports a biology-driven framework for cancer classification and treatment, moving beyond traditional histological boundaries. Full article

(This article belongs to the Section Molecular Cancer Biology)

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Graphical abstract

13 pages, 440 KB

Open AccessReview

Complete Mesocolic Excision for Colon Cancer: Insight into Potential Mechanisms of Oncologic Benefit

by Fotios Seretis, Antonia Panagaki, Charalambos Seretis, Maria Sotiropoulou, Michail Psarologos, Nikolaos Mamakos, Konstantinos Polyzois, Vasileios Drakopoulos and Stylianos Kapiris

Cancers 2025, 17(16), 2719; https://doi.org/10.3390/cancers17162719 - 21 Aug 2025

Viewed by 680

Abstract

Background/Objectives: Complete mesocolic excision (CME) has recently been proposed as a radical operation for the treatment of colon cancer. Increasing evidence suggests a survival benefit from this operation, although the exact reasons for this remain largely unknown. Methods: We have undertaken a comprehensive [...] Read more.

Background/Objectives: Complete mesocolic excision (CME) has recently been proposed as a radical operation for the treatment of colon cancer. Increasing evidence suggests a survival benefit from this operation, although the exact reasons for this remain largely unknown. Methods: We have undertaken a comprehensive review of the literature in PubMed and Embase databases, examining the potential mechanisms explaining this oncologic benefit. Results: Complete mesocolic excision with central vascular ligation appears to improve the rates of radial margin negativity and is associated with increased lymph node yield and improved staging for colon cancer patients by removal of apical lymph nodes and removal of skip metastasis. The en bloc removal of the cancer-related mesentery along the interfascial plane between the mesocolon and retroperitoneal structures removes en bloc tumor deposits that appear to have a significant negative effect on cancer prognosis, irrespective of lymph node status. CME is associated with decreased rates of local recurrence and improved disease-free and overall survival. The existing literature suffers from a lack of data on molecular pathology and integration of prognostic pathologic factors such as tumor deposits in patients undergoing complete mesocolic excision. Conclusions: CME confers significant benefits in terms of local control of the disease and improves cancer-specific survival. Further research on the matter is necessary to incorporate prognostic pathologic and molecular parameters. Full article

(This article belongs to the Special Issue The Surgical Management of Colorectal Cancer)

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44 pages, 919 KB

Open AccessSystematic Review

Postoperative Pain Following Gynecology Oncological Surgery: A Systematic Review by Tumor Site

by Selina Chiu, Helen Staley, Xiaoxi Zhang, Anita Mitra, Flavia Sorbi, James Richard Smith, Joseph Yazbek, Sadaf Ghaem-Maghami, Sanooj Soni, Christina Fotopoulou and Srdjan Saso

Cancers 2025, 17(16), 2718; https://doi.org/10.3390/cancers17162718 - 21 Aug 2025

Viewed by 1175

Abstract

Introduction: Postoperative pain management is complex and crucial in major gynecology oncological surgery. Currently, there is no well-defined standardized approach, resulting in significant variability in practices worldwide. This systematic review evaluates the effectiveness of analgesic strategies used postoperatively in gynecological cancer surgery. Methods: [...] Read more.

Introduction: Postoperative pain management is complex and crucial in major gynecology oncological surgery. Currently, there is no well-defined standardized approach, resulting in significant variability in practices worldwide. This systematic review evaluates the effectiveness of analgesic strategies used postoperatively in gynecological cancer surgery. Methods: A systematic review was conducted from inception to June 26th 2024 to identify all randomized controlled trials (RCTs) assessing pain management following any surgery for gynecological cancer. This was performed on the CENTRAL, PubMed, Embase, and MEDLINE databases. Results: A total of 46 RCTs met the inclusion criteria. Of these 5316 patients, 1844 patients had cervical cancer, 99 had endometrial cancer, and 158 had ovarian cancer. The remaining 3215 participants had unspecified gynecological cancers or benign pathology. No studies focused on postoperative analgesia for vulval cancer. A meta-analysis was not feasible due to heterogeneity in study design, analgesic interventions (i.e., opioids, local anesthetics, paracetamol, NSAIDs, and holistic and complementary therapies), and multiple routes of administration (i.e., oral, parenteral, regional, neuraxial, local infiltration, intraperitoneal, intramuscular, patient-controlled, topical, and rectal). No single analgesic modality demonstrated clear superiority. The median Jadad score for methodological quality of the included trials was 4. Conclusions: The limited cancer-specific RCTs and diversity of analgesia modalities utilized reflect the wide range of applications. Postoperative pain is multifactorial and cannot be adequately managed with a single agent. National and international guidelines should aim to establish a standardized framework for postoperative pain management in gynecological cancers, ensuring accessible, evidence-based care that enhances both short- and long-term patient quality of life. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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22 pages, 4086 KB

Open AccessArticle

Comprehensive Longitudinal Linear Mixed Modeling of CTCs Illuminates the Role of Trop2, EpCAM, and CD45 in CTC Clustering and Metastasis

by Seth D. Merkley, Huining Kang, Ursa Brown-Glaberman and Dario Marchetti

Cancers 2025, 17(16), 2717; https://doi.org/10.3390/cancers17162717 - 21 Aug 2025

Viewed by 1595

Abstract

Background/Objectives: Breast cancer is the most commonly diagnosed cancer worldwide, with high rates of distant metastasis. While circulating tumor cells (CTCs) are the disseminatory units of metastasis and are indicative of a poor prognosis, CTC heterogeneity within individual patients, among breast cancer [...] Read more.

Background/Objectives: Breast cancer is the most commonly diagnosed cancer worldwide, with high rates of distant metastasis. While circulating tumor cells (CTCs) are the disseminatory units of metastasis and are indicative of a poor prognosis, CTC heterogeneity within individual patients, among breast cancer subtypes, and between primary and metastatic tumors within a patient obscures the relationship between CTCs and disease progression. EpCAM, its homolog Trop2, and a pan-Cytokeratin marker were evaluated to determine their contributions to CTC presence and clustering over the study period. We conducted a systematic longitudinal analysis of 51 breast cancer patients during the course of their treatment to deepen our understanding of CTC contributions to breast cancer progression. Methods: 272 total blood samples from 51 metastatic breast cancer (mBC) patients were included in the study. Patients received diverse treatment schedules based on discretion of the practicing oncologist. Patients were monitored from July 2020 to March 2023, with blood samples collected at scheduled care appointments. Nucleated cells were isolated, imaged, and analyzed using Rarecyte^® technology, and statistical analysis was performed in R using the lmerTest and lme4 packages, as well as in Graphpad Prism version 10.4.1. Results: Both classical CTCs (DAPI+, EpCAM+, CK+, CD45– cells) and Trop2+ CTCs were detected in the blood of breast cancer patients. A high degree of correlation was found between CTC biomarkers, and CTC expression of EpCAM, Trop2, and the presence of CD45+ cells, all predicted cluster size, while Pan-CK did not. Furthermore, while analyses of biomarkers by receptor status revealed no significant differences among HR+, HER2+, and TNBC patients, longitudinal analysis found evidence for discrete trajectories of EpCAM, Trop2, and clustering between HR+ and HER2+ cancers after diagnosis of metastasis. Conclusions: Correlation and longitudinal analysis revealed that EpCAM+, Trop2+, and CD45+ cells were predictive of CTC cluster presence and size, and highlighted distinct trajectories of biomarker change over time between HR+ and HER2+ cancers following metastatic diagnosis. Full article

(This article belongs to the Special Issue Circulating Tumor Cells (CTCs) and the Implementation of Liquid Biopsy (2nd Edition))

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13 pages, 234 KB

Open AccessArticle

Predictors of Successful Whole-Body Hyperthermia in Cancer Patients: Target Temperature Achievement and Safety Analysis

by Anna Lena Hohneck, Vivien Schmitz-Solheid, Deniz Gencer, Maik Schroeder, Hartmut Riess, Annette Gerhards, Iris Burkholder, Stefan Heckel-Reusser, Julia Gottfried and Ralf-Dieter Hofheinz

Cancers 2025, 17(16), 2716; https://doi.org/10.3390/cancers17162716 - 21 Aug 2025

Viewed by 947

Abstract

Aim: This study aimed to investigate the effectiveness and safety of whole-body hyperthermia (WBH) in cancer patients, identifying predictive factors for successful treatment (reaching target temperature ≥ 38.5 °C) and assessing adverse effects. Methods: We conducted a retrospective analysis of 397 cancer patients [...] Read more.

Aim: This study aimed to investigate the effectiveness and safety of whole-body hyperthermia (WBH) in cancer patients, identifying predictive factors for successful treatment (reaching target temperature ≥ 38.5 °C) and assessing adverse effects. Methods: We conducted a retrospective analysis of 397 cancer patients receiving a total of 855 WBH treatment sessions at a single institution between January 2018 and December 2018. Results: A total of 855 WBH treatments were performed on 397 patients (76.6% female; median age 58 years). The most common cancer types included breast cancer (52.4%), followed by prostate cancer (13.1%) and gynecological cancers (10.6%), with 54.7% of patients having metastatic disease. Target temperature was reached in 90.1% (770 of 855) of sessions, with a median treatment time of 202 min and maximum temperature of 40.4 °C. Common side effects included headache (54.9%), skin reactions (11.7%), and cardiac effects (9.4%), with no serious adverse events. Serum creatinine (p = 0.01, OR 0.30, 95% CI: 0.11–0.78) and secale cornutum/galena co-medication during WBH (p < 0.001, OR 0.26 [0.12, 0.54]) emerged as independent predictors of achieving target temperature in multivariate analysis. Both elevated creatinine levels and the use of secale cornutum/galena were associated with an approximately 70% lower probability of achieving the target temperature. Conclusions: WBH demonstrates safety in cancer patients with high success rates in reaching target temperatures. Both elevated creatinine levels and the use of secale cornutum/galena were associated with a lower chance of reaching the target temperature and thus impacting and predicting WBH success. Full article

(This article belongs to the Special Issue Integrated Management of Cancer (2nd Edition))

24 pages, 2384 KB

Open AccessReview

Amplification-Free Testing of microRNA Biomarkers in Cancer

by Bahareh Soleimanpour, Juan Jose Diaz Mochon and Salvatore Pernagallo

Cancers 2025, 17(16), 2715; https://doi.org/10.3390/cancers17162715 - 21 Aug 2025

Viewed by 569

Abstract

Background: Circulating miRNAs have been identified as potential biomarkers for the early diagnosis and monitoring of cancers. However, limitations of polymerase chain reaction (PCR)-based methods are currently delaying the transition of miRNA research into clinical practice. These include labour-intensive workflows, exposure to errors [...] Read more.

Background: Circulating miRNAs have been identified as potential biomarkers for the early diagnosis and monitoring of cancers. However, limitations of polymerase chain reaction (PCR)-based methods are currently delaying the transition of miRNA research into clinical practice. These include labour-intensive workflows, exposure to errors and difficulties in detecting and quantifying low-abundance miRNAs. Objectives: This review emphasizes the need to develop amplification-free (“PCR-free”) technologies to improve the reliability, scalability and practicality of miRNA diagnostics in clinical settings. Methods: This review explores recent advances in PCR-free technologies developed over the past five years. It focuses on innovative methods, such as bead-based assays and sensor detection platforms, which serve as valuable alternatives to conventional PCR-based approaches. These emerging technologies have the potential to overcome the key limitations of PCR by offering streamlined workflows, reduced error rates and enhanced compatibility with a variety of clinical sample types. Crucially, they enable absolute quantification without the need for pre-nucleic acid extraction, reverse transcription or amplification, as well as the simultaneous detection of multiple miRNAs within a single assay. These provide cost-effective and scalable solutions for comprehensive biomarker profiling. The transition from PCR-based to PCR-free technologies is a significant step forward in miRNA diagnostics, overcoming long-standing technical barriers and paving the way for broader adoption of miRNA analysis in routine clinical settings. This shift supports the advancement of precision medicine and holds promises for improving early cancer detection. Full article

(This article belongs to the Section Cancer Biomarkers)

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23 pages, 4542 KB

Open AccessArticle

Targeting NRF2 and FSP1 to Overcome Ferroptosis Resistance in TSC2-Deficient and Cancer Cells

by Tasmia Tahsin, Darius K. McPhail, Jesse D. Champion, Mohammad A. M. Alzahrani, Madeleine L. Hilditch, Alexandre Faris-Orr, Brian L. Calver, James G. Cronin, Juan C. Mareque-Rivas, Darren W. Sexton, Stephen Fôn Hughes, Robert Steven Conlan, David Mark Davies and Andrew R. Tee

Cancers 2025, 17(16), 2714; https://doi.org/10.3390/cancers17162714 - 21 Aug 2025

Viewed by 1120

Abstract

Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we [...] Read more.

Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 312 KB

Open AccessArticle

Robust Permutation Test of Intraclass Correlation Coefficient for Assessing Agreement

by Mengyu Fang, Alan David Hutson and Han Yu

Cancers 2025, 17(16), 2713; https://doi.org/10.3390/cancers17162713 - 21 Aug 2025

Viewed by 486

Abstract

Background: Inter-rater reliability is critical in oncology to ensure consistent and reliable measurements across raters and methods, such as when evaluating biomarker levels in different laboratories or comparing tumor size assessments by radiation oncologists during therapy planning. This consistency is essential for informed [...] Read more.

Background: Inter-rater reliability is critical in oncology to ensure consistent and reliable measurements across raters and methods, such as when evaluating biomarker levels in different laboratories or comparing tumor size assessments by radiation oncologists during therapy planning. This consistency is essential for informed decision-making in both clinical and research contexts, and the intraclass correlation coefficient (ICC) is a widely recommended statistic for assessing agreement. This work focuses on hypothesis testing of the ICC(2,1) with two raters. Methods: We evaluated the performance of a naive permutation test for testing the hypothesis

H_{0} : ICC = 0

and found that it fails to reliably control the type I error rate. To address this, we developed a robust permutation test based on a studentized statistic, which we prove to be asymptotically valid even when paired variables are uncorrelated but dependent. Results: Simulation studies demonstrate that the proposed test consistently maintains type I error control, even with small sample sizes, outperforming the naive approach across various data-generating scenarios. Conclusions: The proposed studentized permutation test for ICC(2,1) offers a statistically valid and robust method for assessing inter-rater reliability and demonstrates practical utility when applied to two real-world oncology datasets. Full article

(This article belongs to the Special Issue Application of Biostatistics in Cancer Research)

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19 pages, 972 KB

Open AccessArticle

Baseline Hemostatic Biomarker Assessment Identifies Breast Cancer Patients at High Risk for Venous Thromboembolism During Chemotherapy

by Marina Marchetti, Patricia Gomez-Rosas, Laura Russo, Carmen Julia Tartari, Silvia Bolognini, Chiara Ticozzi, Debora Romeo, Francesca Schieppati, Luca Barcella, Roberta Sarmiento, Giovanna Masci, Giampietro Gasparini, Filippo De Braud, Carlo Tondini, Armando Santoro, Fausto Petrelli, Francesco Giuliani, Andrea D’Alessio, Roberto Labianca and Anna Falanga

Cancers 2025, 17(16), 2712; https://doi.org/10.3390/cancers17162712 - 20 Aug 2025

Viewed by 650

Abstract

(1) Background: The presence of metastatic disease significantly increases the risk of venous thromboembolism (VTE) in breast cancer, particularly during chemotherapy. Although not categorized as a highly thrombogenic malignancy, the elevated global prevalence of this cancer places a substantial number of patients at [...] Read more.

(1) Background: The presence of metastatic disease significantly increases the risk of venous thromboembolism (VTE) in breast cancer, particularly during chemotherapy. Although not categorized as a highly thrombogenic malignancy, the elevated global prevalence of this cancer places a substantial number of patients at risk of thrombosis, which cannot yet be accurately predicted by validated risk assessment models (RAMs), highlighting the need for a dedicated model. (2) Aim: This study aims to develop a RAM for VTE in newly diagnosed metastatic breast cancer patients enrolled in a prospective, observational, and multicenter study. (3) Methods: A cohort of 189 patients beginning antitumor therapy were enrolled and prospectively monitored for VTE and mortality. Blood samples collected at enrollment were tested for D-dimer, fibrinogen, FVIII, prothrombin fragment 1 + 2 (F1 + 2), and thrombin generation (TG). Competing risk analyses were performed to identify significant predictors. (4) Results: Within one year, the cumulative incidences of VTE and mortality were 7.0% and 12%, respectively. Univariable analysis identified high Ki-67, D-dimer, FVIII, fibrinogen, and TG levels, along with low hemoglobin levels, as independent predictors of VTE. Only Ki-67, fibrinogen, FVIII, and hemoglobin were retained as significant predictors in multivariable analysis. These variables were further examined by multiple linear regression, which revealed Ki-67 and fibrinogen as the most significant parameters. A continuous RAM was then developed based on Ki-67 and fibrinogen (c-statistics 0.78), categorizing patients into low-risk and high-risk groups for VTE (2% vs. 13%; SHR 3.6, p = 0.018). This stratification could not be achieved using currently validated models for VTE risk. (5) Conclusions: We developed an accurate RAM for VTE that enables the identification of metastatic breast cancer patients at high risk for VTE, which supports clinicians in personalized thromboprophylaxis strategies if externally validated. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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20 pages, 589 KB

Open AccessArticle

Machine Learning-Based Classification of Cervical Lymph Nodes in HNSCC: A Radiomics Approach with Feature Selection Optimization

by Sara Naccour, Assaad Moawad, Matthias Santer, Daniel Dejaco and Wolfgang Freysinger

Cancers 2025, 17(16), 2711; https://doi.org/10.3390/cancers17162711 - 20 Aug 2025

Viewed by 524

Abstract

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) diagnosis and treatment rely heavily on computed tomography (CT) imaging to evaluate tumor characteristics and lymph node (LN) involvement, crucial for staging, prognosis, and therapy planning. Conventional LN evaluation methods based on morphological criteria such [...] Read more.

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) diagnosis and treatment rely heavily on computed tomography (CT) imaging to evaluate tumor characteristics and lymph node (LN) involvement, crucial for staging, prognosis, and therapy planning. Conventional LN evaluation methods based on morphological criteria such as size, shape, and anatomical location often lack sensitivity for early metastasis detection. This study leverages radiomics to extract quantitative features from CT images, addressing the limitations of subjective assessment and aiming to enhance LN classification accuracy while potentially reducing reliance on invasive histopathology. Methods: We analyzed 234 LNs from 27 HNSCC patients, deriving 120 features per node, resulting in over 25,000 data points classified into reactive, pathologic, and pathologic with extracapsular spread classes. Considering the challenges of high dimensionality and limited dataset size, more than 44,000 experiments systematically optimized machine learning models, feature selection methods, and hyperparameters, including ensemble approaches to strengthen classification robustness. A Pareto front strategy was employed to balance diagnostic accuracy with significant feature reduction. Results: The optimal model, validated via 5-fold cross-validation, achieved a balanced accuracy of 0.90, an area under the curve (AUC) of 0.93, and an F1-score of 0.88 using only five radiomics features. Conclusions: This interpretable approach aligns well with clinical radiology practice, demonstrating strong potential for clinical application in noninvasive LN classification in HNSCC. Full article

(This article belongs to the Section Methods and Technologies Development)

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14 pages, 1172 KB

Open AccessArticle

A Comprehensive Genomic Analysis of Nucleophosmin (NPM1) in Acute Myeloid Leukemia

by Osama Batayneh, Mahmoudreza Moein, Alexandra Goodman, Devashish Desai, Dean Pavlick, Chelsea Marcus, Caleb Ho, Russell Madison, Richard S. P. Huang, Jeffrey S. Ross, Teresa Gentile, Zheng Zhou and Krishna Bilas Ghimire

Cancers 2025, 17(16), 2710; https://doi.org/10.3390/cancers17162710 - 20 Aug 2025

Viewed by 616

Abstract

Background/Objectives: This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy. Methods: [...] Read more.

Background/Objectives: This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy. Methods: A total of 4206 AML cases from 2019 to 2024 were analyzed using the FoundationOne Heme assay, incorporating comprehensive DNA and RNA sequencing. Patients were stratified into NPM1mut and NPM1wt cohorts, and genomic differences were systematically compared between the two groups. Results: Among 4206 cases, 633 (15.1%) featured NPM1 GA, with over 99% exhibiting short variant mutations. NPM1mut AML was more common in females (53.4% vs. 41.5%) and associated with a slightly higher median age (62 vs. 60 years). GA was more frequent in NPM1mut AML compared to the NPM1wt and included DNMT3A (39.2% vs. 12.6%; p < 0.0001), PTPN11 (18.3% vs. 7.5%; p < 0.0001), FLT3 (54.5% vs. 14.7%; p < 0.0001), IDH1 (16.1% vs. 5.6%; p < 0.0001), IDH2 (19.0% vs. 9.0%; p < 0.0001), TET2 (23.4% vs. 13.5%; p < 0.0001), and WT1 (12.5% vs. 9.4%; p = 0.02). GA was more frequent in NPM1wt AML and included ASXL1 (17.1% vs. 3.6%; p 0.0001), BCOR (7.5% vs. 1.6%; p < 0.0001), KMT2A (14.7% vs. 0.2%; p < 0.0001), RUNX1 (22.5% vs. 1.9%; p 0.0001), STAG2 (6.9% vs. 1.6%; p < 0.0001) and TP53 (19.1% vs. 4.1%; p < 0.0001). Conclusions: Mutations linked to therapy targets in AML, such as (FLT3 and IDH1/2), PTPN11, and DNMT3A (both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereas KMT2A, TP53, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML. Full article

(This article belongs to the Section Cancer Therapy)

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14 pages, 3185 KB

Open AccessArticle

Cumulative Dose Analysis in Adaptive Carbon Ion Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer

by Zhuojun Ju, Makoto Sakai, Xiangdi Meng, Nobuteru Kubo, Hidemasa Kawamura and Tatsuya Ohno

Cancers 2025, 17(16), 2709; https://doi.org/10.3390/cancers17162709 - 20 Aug 2025

Viewed by 496

Abstract

Objectives: This study aimed to assess the precision of dose delivery to the target in adaptive carbon ion radiotherapy (CIRT) for locally advanced non-small cell lung cancer (LA-NSCLC) in cumulative dosimetry. Methods: Forty-six patients who received CIRT were included (64 Gy[relative biological [...] Read more.

Objectives: This study aimed to assess the precision of dose delivery to the target in adaptive carbon ion radiotherapy (CIRT) for locally advanced non-small cell lung cancer (LA-NSCLC) in cumulative dosimetry. Methods: Forty-six patients who received CIRT were included (64 Gy[relative biological effectiveness, RBE] in 16 fractions) with treatment plan computed tomography (CT) and weekly CT scans. Offline adaptive radiotherapy (ART) was administered if the dose distribution significantly worsened. Daily doses were calculated from weekly CTs and integrated into plan CT scans using deformable image registration. The dosimetry parameters were compared between the as-scheduled plan and adaptive replan in patients receiving ART. Survival outcomes and toxicity were compared between the ART and non-ART groups. Results: ART was implemented for 27 patients in whom adaptive replans significantly increased the median V_98% of the clinical tumor volume from 96.5% to 98.1% and D_98% from 60.5 to 62.7 Gy(RBE) compared with the as-scheduled plans (p < 0.001). The conformity and uniformity of the dose distribution improved (p < 0.001), with no significant differences in the doses to normal tissues (lungs, heart, esophagus, and spinal cord) from the as-scheduled plans (p > 0.05). The ART and non-ART groups demonstrated comparable local control, progression-free survival, and overall survival (p > 0.05). No grade 3 or higher radiation-related toxicities were observed. Conclusions: ART enhanced target dose coverage while maintaining acceptable normal tissue exposure, supporting weekly CT monitoring integration during CIRT for the timely intervention for anatomical variations, ensuring precise dose delivery in LA-NSCLC. Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

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14 pages, 2586 KB

Open AccessArticle

MR-Guided Radiation Therapy for Prostate and Pancreas Cancer Treatment: A Dosimetric Study Across Two Major MR-Linac Platforms

by Huiming Dong, Jonathan Pham, Michael V. Lauria, Caiden Atienza, Brett Sloman, Paul Barry, Jennifer Davis, Michael Saracen, Amar Kishan, Ann Raldow, X. Sharon Qi, Daniel Hyer and James Lamb

Cancers 2025, 17(16), 2708; https://doi.org/10.3390/cancers17162708 - 20 Aug 2025

Viewed by 682

Abstract

Background/Objectives: MR-guided radiation therapy (MRgRT) has rapidly evolved into an important treatment modality, with the Elekta Unity and ViewRay MRIdian systems being two major MR-linac platforms. Despite the shared concept of MRgRT, the two platforms elected different system designs that could potentially impact [...] Read more.

Background/Objectives: MR-guided radiation therapy (MRgRT) has rapidly evolved into an important treatment modality, with the Elekta Unity and ViewRay MRIdian systems being two major MR-linac platforms. Despite the shared concept of MRgRT, the two platforms elected different system designs that could potentially impact the dosimetric characteristics and quality of a treatment. In this study, we aim to perform a comparative dosimetric investigation between these two MR-linac systems in prostate and pancreas cancers. Methods: Dosimetric characteristics were evaluated by retrospectively re-creating 20 clinical prostate and pancreas cases originally treated on MRIdian using the Unity system, adhering to MIRAGE and SMART clinical trial constraints. Treatment plans were re-created with matching planning images, structures, beam geometry, and dose parameters. To ensure comparison consistency, all Unity treatment plans were normalized to match the target coverage of the MRIdian counterparts, and the organ-at-risk (OAR) dose was investigated. Results: Most OARs’ dose-volume metrics showed no statistically significant differences. For prostate patients, Unity demonstrated lower rectum V36Gy (p = 0.0095), V38Gy (p = 0.0043), V40Gy (p = 0.0469), and lower left (p = 0.0137) and right femur V20Gy (p = 0.0020). For pancreas patients, Unity plans had a lower mean liver dose (p = 0.0371). All Unity plans had a Gamma passing rate > 90%, confirming the clinical deliverability. Mean delivery times were 12.78 ± 1.68 and 13.53 ± 1.88 min for MRIdian and Unity prostate plans, respectively, and 14.58 ± 2.78 and 17.40 ± 3.77 min for MRIdian and Unity pancreas plans, respectively. Conclusions: Overall, comparable treatment quality and delivery times were observed between the two platforms. Full article

(This article belongs to the Section Methods and Technologies Development)

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13 pages, 638 KB

Open AccessArticle

Conditional Survival in Patients with Locally Advanced Rectal Cancer and Pathologic Complete Response: Results from an Observational Retrospective Multicenter Long-Term Follow-Up Study

by Carlos Cerdán Santacruz, Oscar Cano-Valderrama, Laura Melina Fernández, Ramón Sanz-Ongil, Rocío Santos Rancaño, Miquel Kraft Carre, Francisco Blanco Antona, Inés Aldrey Cao, Alba Correa Bonito, Jesús Cifuentes, Antoni Codina-Cazador, Eloy Espín-Basany, Eduardo García-Granero and Blas Flor Lorente

Cancers 2025, 17(16), 2707; https://doi.org/10.3390/cancers17162707 - 20 Aug 2025

Viewed by 527

Abstract

Introduction/Background: Patients with locally advanced rectal cancer (LARC) with pathological complete response (pCR) after neoadjuvant chemo-radiotherapy (NCRT) are a privileged group because of the favorable progression of their disease. However, their follow-up patterns after surgery are similar to those of other groups [...] Read more.

Introduction/Background: Patients with locally advanced rectal cancer (LARC) with pathological complete response (pCR) after neoadjuvant chemo-radiotherapy (NCRT) are a privileged group because of the favorable progression of their disease. However, their follow-up patterns after surgery are similar to those of other groups with worse prognosis, with the consequent psychological and economic impact. Methods: This is a retrospective observational multicenter study with data obtained from the Spanish Rectal Cancer Project. Patients with LARC who underwent surgery with curative intent after NCRT and achieved pCR were selected. The last follow-up update was conducted in December 2021. A conditional survival model was used to analyze oncological outcomes during follow-up. Recurrence-free survival (RFS) was analyzed for the entire cohort of patients and for those who survived at one, two, and three years. Results: A total of 815 patients from 32 hospitals were included. Their mean age was 65.1 years, and 36.1% of them were women. Of the 815 patients, 35 died or experienced recurrence (local or systemic) in the first postoperative year, and 780 were included in the conditional survival analysis one year after surgery. The probability of RFS at 5 years was 86.5% in the whole cohort and 89.4%, 92.9%, and 95.2% for survivors at one, two, and three years, respectively. The probability of recurrence in these same groups was 6.5%, 4.3%, 1.8%, and 0.6%. Conclusions: Follow-up of patients with LARC and pCR after NCRT followed by surgery could be adapted based on conditional survival data showing that the probability of RFS increases as patients remain recurrence-free, and recurrences more than 3 years after treatment are exceptional. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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18 pages, 2776 KB

Open AccessArticle

A Priori Prediction of Breast Cancer Response to Neoadjuvant Chemotherapy Using CT Radiomics

by Deok Hyun Jang, Laurentius O. Osapoetra, Lakshmanan Sannachi, Belinda Curpen, Ana Pejović-Milić and Gregory J. Czarnota

Cancers 2025, 17(16), 2706; https://doi.org/10.3390/cancers17162706 - 20 Aug 2025

Viewed by 541

Abstract

(1) Background: Response to neoadjuvant chemotherapy (NAC) is a key prognostic indicator in breast cancer. However, current response evaluation methods rely on histopathological assessment after surgery, delaying opportunities for early treatment adaptation. This study aimed to develop a machine learning model by integrating [...] Read more.

(1) Background: Response to neoadjuvant chemotherapy (NAC) is a key prognostic indicator in breast cancer. However, current response evaluation methods rely on histopathological assessment after surgery, delaying opportunities for early treatment adaptation. This study aimed to develop a machine learning model by integrating radiomic features extracted from pre-treatment, contrast-enhanced computed tomography (CT) images with baseline clinical variables to predict NAC response before therapy initiation. (2) Methods: The study investigated two categories of response: (i) pathologic complete response (pCR) versus non-pCR, and (ii) clinical response versus non-response, where clinical response was defined as a reduction in tumor size of at least 30%, encompassing both complete and partial responses. Radiomic features (n = 214) were extracted from intratumoral and peritumoral regions of pre-treatment CT images. Clinical variables (n = 7) were also incorporated to enhance predictive capability. A predictive model was developed using XGBoost algorithm, and performance was evaluated across ten independent data partitions using metrics including accuracy, precision, sensitivity, specificity, F1-score, and AUC. (3) Results: A total of 177 patients were enrolled in the study. The combined clinical-radiomic model set exhibited superior predictive performance compared to models based solely on either radiomic or clinical features. For pCR classification, integrating clinical and radiomic features produced the strongest model, achieving 82.8% accuracy with an AUC of 0.846. The clinical model alone reached 71.4% accuracy and an AUC of 0.797, while the radiomic model achieved 67.5% accuracy and an AUC of 0.615. For clinical response classification, the combined model again outperformed the individual models, achieving 71.7% accuracy with an AUC of 0.725, compared with 65.0% accuracy and an AUC of 0.666 for the clinical model, and 65.6% accuracy with an AUC of 0.615 for the radiomic model. (4) Conclusions: These results demonstrate that integrating CT radiomic features with clinical information enhances the prediction of NAC response, supporting the potential for earlier and more personalized therapeutic decision-making in breast cancer management. Full article

(This article belongs to the Section Cancer Biomarkers)

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9 pages, 712 KB

Open AccessArticle

Cutaneous Melanoma and Occupational UV Exposure: Associations with Anatomical Site, Histological Subtype, and Breslow Thickness

by Vincenzo De Giorgi, Silvia Viscera, Giovanni Cecchi, Elisabetta Magnaterra, Veronica Traversini, Gabriella Perillo, Biancamaria Zuccaro, Federica Fazzari, Antonio Baldassarre, Stefano Dugheri and Nicola Mucci

Cancers 2025, 17(16), 2705; https://doi.org/10.3390/cancers17162705 - 20 Aug 2025

Viewed by 558

Abstract

Background: The relationship between occupational sun exposure and melanoma risk is complex and multifaceted, with existing evidence yielding contradictory findings. Unlike Non-Melanoma Skin Cancer (NMSC), for which occupational sun exposure is a well-established risk factor, the link with cutaneous melanoma remains contentious. Objectives: [...] Read more.

Background: The relationship between occupational sun exposure and melanoma risk is complex and multifaceted, with existing evidence yielding contradictory findings. Unlike Non-Melanoma Skin Cancer (NMSC), for which occupational sun exposure is a well-established risk factor, the link with cutaneous melanoma remains contentious. Objectives: This study aimed to evaluate whether, in a cohort of patients with cutaneous melanoma, an association existed between occupational sun exposure and melanoma, specifically with histotype, site of occurrence, and Breslow index. Methods: This is a retrospective cohort analysis conducted to evaluate whether occupational sun exposure constitutes a risk factor for the development of cutaneous melanoma in patients diagnosed between January 2005 and October 2023 at the Dermatology Unit, Azienda USL Toscana Centro, Florence. Occupational ultraviolet (UV) exposure was examined by classifying each participant’s job into categories based on solar UV exposure levels—outdoor (e.g., agriculture and construction roles), mixed indoor/outdoor (e.g., trades and public safety professions), and indoor settings (e.g., office-based work). Results: A final total of 1417 patients were analyzed. Occupational categorization revealed that 1171 patients (82.64%) were classified as non-occupationally exposed (indoor), while 246 (17.36%) were occupationally exposed to solar UV radiation (including 14.82% mixed indoor/outdoor and 2.54% outdoor workers). A significant association was observed between occupational sun exposure and lentigo maligna, which was more prevalent among exposed workers and even more so in the outdoor subgroup. Anatomical site distribution exhibited a significant association with occupational sun exposure. Indeed occupationally exposed individuals showed a higher prevalence of melanomas in the head and neck region, a distribution pattern particularly evident among outdoor workers, suggesting that these sites may be more susceptible to chronic sun exposure in outdoor and mixed occupations. Moreover, a significant association was found between occupational exposure and Breslow thickness, with exposed workers presenting with thicker melanomas at diagnosis, suggesting more advanced disease. Conclusions: The finding of this study may reflect variations in occupational sun exposure patterns and warrants further investigation into protective measures and early-detection strategies tailored to occupational groups. Full article

(This article belongs to the Section Clinical Research of Cancer)

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16 pages, 589 KB

Open AccessArticle

The Cervical Lymph Node Positive Metastatic Probability Is a Significant Predictor of Survival for Oral Squamous Cell Carcinoma—A Nationwide Study

by Li-Jen Liao, Cheng-Lin Lu, Yu-Ping Cheng, Ping-Chia Cheng, Yong-Chen Chen, Chun-Ju Chiang, Wen-Chung Lee, San-Lin You and Wan-Lun Hsu

Cancers 2025, 17(16), 2704; https://doi.org/10.3390/cancers17162704 - 20 Aug 2025

Viewed by 492

Abstract

Background/Objectives: This study aimed to evaluate the prognostic significance of lymph node density (LND) and the log odds of positive lymph nodes (LODDS) in patients with oral squamous cell carcinoma (OSCC) using a nationwide database. Methods: A retrospective cohort study was conducted using [...] Read more.

Background/Objectives: This study aimed to evaluate the prognostic significance of lymph node density (LND) and the log odds of positive lymph nodes (LODDS) in patients with oral squamous cell carcinoma (OSCC) using a nationwide database. Methods: A retrospective cohort study was conducted using the Taiwan Cancer Registry to identify patients diagnosed with OSCC who underwent surgery for both the primary tumor and neck dissection. Clinicopathological variables were collected, and survival outcomes were analyzed using Cox proportional hazards models. LND was categorized as negative, <0.05, and ≥0.05; LODDS was grouped into four categories: <−4, −4 to −3.5, −3.5 to −2.5, and ≥−2.5. Results: A total of 1643 female and 15,475 male patients were included, with a mean age of 57.4 years (range, 20–98 years). In multivariable Cox regression analyses, LND and LODDS were identified as independent prognostic factors for overall survival. Compared with patients with negative LND, the hazard ratios for LND < 0.05 and LND ≥0.05 were 2.12 (95% CI, 1.90–2.36) and 3.35 (95% CI, 3.05–3.67), respectively (p < 0.01). Similarly, relative to the lowest LODDS group (<−4), the hazard ratios for the higher categories were 1.51 (95% CI, 1.32–1.74) for −4 to −3.5, 2.30 (95% CI, 2.05–2.57) for −3.5 to −2.5, and 4.32 (95% CI, 3.85–4.86) for ≥−2.5 (p < 0.01). Conclusions: LND and LODDS are significant prognostic indicators in OSCC. Incorporating these lymph node–based metrics into prognostic models may enhance risk stratification and inform clinical decision-making. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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12 pages, 876 KB

Open AccessArticle

Development of a Cytogenetic Double-Hit Model for Survival Prediction in Multiple Myeloma

by Chenxing Du, Jian Cui, Jingyu Xu, Wenqiang Yan, Lingna Li, Weiwei Sui, Shuhui Deng, Shuhua Yi, Yan Xu, Chengwen Li, Jiawei Zhao, Dehui Zou, Lugui Qiu and Gang An

Cancers 2025, 17(16), 2703; https://doi.org/10.3390/cancers17162703 - 20 Aug 2025

Viewed by 622

Abstract

Background: High-risk chromosomal abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH) have a well-established adverse prognostic impact in multiple myeloma (MM). It is increasingly recognized that the coexistence of two or more HRCAs identifies a particularly poor-risk subgroup, often referred to as [...] Read more.

Background: High-risk chromosomal abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH) have a well-established adverse prognostic impact in multiple myeloma (MM). It is increasingly recognized that the coexistence of two or more HRCAs identifies a particularly poor-risk subgroup, often referred to as double- or multiple-hit MM. However, there is currently no consensus on its definition. Methods: We retrospectively analyzed a multicenter cohort of 1122 newly diagnosed MM patients from 2008 to 2019. Double-hit MM was defined as the coexistence of at least two of the following four HRCAs: t(14;16), gain(1q), del(17p), and del(1p). Based on this definition, we constructed a novel prognostic model, the HBDH (Institute of Hematology & Blood Diseases Hospital) double-hit model, and assessed its prognostic value for progression-free survival (PFS) and overall survival (OS). Results: According to the HBDH model, double-hit patients showed significantly inferior outcomes compared to non-double-hit patients, with median PFS of 20.6 vs. 53.3 months (p < 0.001) and median OS of 40.2 vs. 84.2 months (p < 0.001). The addition of del(13q), t(4;14), or t(11;14) did not improve the prognostic performance of the model. Importantly, the HBDH model was independent of the International Staging System (ISS), elevated LDH, and advanced age. Conclusions: The HBDH double-hit model identifies a subset of ultra-high-risk MM patients carrying at least two major HRCAs, providing a simple and robust framework for prognostic stratification and a potential reference for future biologically driven treatment approaches. Full article

(This article belongs to the Special Issue Myeloma: Pathogenesis and Targeted Therapies)

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19 pages, 1779 KB

Open AccessReview

Current and Emerging Fluorescence-Guided Techniques in Glioma to Enhance Resection

by Trang T. T. Nguyen, Hayk Mnatsakanyan, Eunhee Yi and Christian E. Badr

Cancers 2025, 17(16), 2702; https://doi.org/10.3390/cancers17162702 - 19 Aug 2025

Viewed by 555

Abstract

Maximal safe surgical resection remains a critical component of glioblastoma (GBM) management, improving both survival and quality of life. However, complete tumor removal is hindered by the infiltrative nature of GBM and its proximity to eloquent brain regions. Fluorescence-guided surgery (FGS) has emerged [...] Read more.

Maximal safe surgical resection remains a critical component of glioblastoma (GBM) management, improving both survival and quality of life. However, complete tumor removal is hindered by the infiltrative nature of GBM and its proximity to eloquent brain regions. Fluorescence-guided surgery (FGS) has emerged as a valuable tool to enhance intraoperative tumor visualization and optimize resection outcomes. Currently used fluorophores such as 5-aminolevulinic acid (5-ALA), fluorescein sodium (FS), and indocyanine green (ICG) have distinct advantages but are limited by suboptimal specificity, shallow tissue penetration, and technical constraints. 5-ALA and SF often yield unreliable signals in low-grade tumors or infiltrative regions and also pose challenges such as phototoxicity and poor depth resolution. In contrast, near-infrared (NIR) fluorescence imaging represents a promising next-generation approach, providing superior tissue penetration, reduced autofluorescence, and real-time delineation of tumor margins. This review explores the mechanisms, clinical applications, and limitations of currently approved FGS agents and highlights future directions in image-guided neurosurgery. Full article

(This article belongs to the Special Issue Research on Fluorescence-Guided Surgery in Cancer Treatment)

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11 pages, 447 KB

Open AccessArticle

Geographical Inequalities and Comorbidities in the Timely Diagnosis of NSCLC: A Real-Life Retrospective Study from a Tertiary Hospital in Western Greece

by Fotios Sampsonas, Pinelopi Bosgana, Emmanouil Psarros, Ourania Papaioannou, Fotini Tryfona, Konstantinos Mantzouranis, Matthaios Katsaras, Ioannis Christopoulos, Georgios Tsirikos, Panagiota Tsiri, Dimitrios Komninos, Electra Koulousousa, Eva Theochari, Vasilina Sotiropoulou, Vasiliki Tzelepi, Vasiliki Zolota, Eleni Kokkotou, Marousa Kouvela, Kostas N. Syrigos and Argyrios Tzouvelekis

Cancers 2025, 17(16), 2701; https://doi.org/10.3390/cancers17162701 - 19 Aug 2025

Viewed by 545

Abstract

Background: Accurate and timely molecular testing in patients with non-small cell lung cancer (NSCLC) is mandatory for targeted therapies and improved outcomes. Real-world obstacles, including geographic distance from specialized lung cancer services, along with comorbidities, may delay molecular diagnosis and subsequent treatment, [...] Read more.

Background: Accurate and timely molecular testing in patients with non-small cell lung cancer (NSCLC) is mandatory for targeted therapies and improved outcomes. Real-world obstacles, including geographic distance from specialized lung cancer services, along with comorbidities, may delay molecular diagnosis and subsequent treatment, therefore hampering survival. Methods: We conducted a retrospective, multi-departmental observational study of 927 patients with newly diagnosed NSCLC that were referred to a tertiary hospital in western Greece between January 2021 and December 2024. Patients were classified based on distance of residence (<30 km vs. ≥30 km). Clinical characteristics, time elapsed from pathological to final molecular diagnosis, and survival outcomes were analyzed and compared. Multivariable Cox regression was used to identify independent predictors of overall survival. Results: Patients residing ≥30 km away (61.2%) experienced delays in molecular testing (median 31 vs. 26 days, p = 0.002) and were less likely to undergo such testing (p = 0.012) compared to those residing <30km. Patients residing >30 km also had a higher prevalence of COPD (42.5% vs. 31.2%, p = 0.002). Median survival from initial pathological diagnosis to death was significantly shorter in non-urban patients (129 vs. 215 days, p = 0.010). A molecular testing delay >35 days was independently associated with worse survival (HR = 0.684, 95% CI: 0.508–0.923, p = 0.013). No differences in TNM stage distribution were observed between geographical groups. Conclusions: Geographic disparities significantly impact access to advanced lung cancer services and molecular diagnostics and may provisionally affect prognosis in NSCLC. Improving testing pathways, incorporating reflex testing in pathological molecular analysis, and optimizing referral systems in rural areas may help to reduce inequalities and improve patient outcomes. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors, Targeted Therapies and Adjuvant Treatment of Lung Cancer)

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25 pages, 433 KB

Open AccessReview

The Quest for Non-Invasive Diagnosis: A Review of Liquid Biopsy in Glioblastoma

by Maria George Elias, Harry Hadjiyiannis, Fatemeh Vafaee, Kieran F. Scott, Paul de Souza, Therese M. Becker and Shadma Fatima

Cancers 2025, 17(16), 2700; https://doi.org/10.3390/cancers17162700 - 19 Aug 2025

Viewed by 849

Abstract

Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour, associated with poor survival outcomes and significant clinical challenges. Conventional diagnostic methods, including MRI, CT, and histopathological analysis of tissue biopsies, are limited by their inability to reliably distinguish [...] Read more.

Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour, associated with poor survival outcomes and significant clinical challenges. Conventional diagnostic methods, including MRI, CT, and histopathological analysis of tissue biopsies, are limited by their inability to reliably distinguish treatment effects from true tumour progression, often resulting in misdiagnosis and delayed intervention. Repeated tissue biopsies are also invasive and unsuitable for longitudinal monitoring. Liquid biopsy, a minimally invasive approach analysing tumour-derived material in biofluids such as blood and cerebrospinal fluid (CSF), offers a promising alternative. This review aims to evaluate current evidence on circulating biomarkers including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), microRNAs (miRNAs), extracellular vesicles (EVs), and proteins in GBM diagnosis and monitoring, and to assess the potential role of artificial intelligence (AI) in enhancing their clinical application. Methods: A narrative synthesis of the literature was undertaken, focusing on studies that have investigated blood- and CSF-derived biomarkers in GBM patients. Key aspects evaluated included biomarker biology, detection techniques, diagnostic and prognostic value, current technical challenges, and progress towards clinical translation. Studies exploring AI and machine learning (ML) approaches for biomarker integration and analysis were also reviewed. Results: Liquid biopsy enables repeated and minimally invasive sampling of tumour-derived material, reflecting the genetic, epigenetic, proteomic, and metabolomic landscape of GBM. Although promising, its translation into routine clinical practice is hindered by the low abundance of circulating biomarkers and lack of standardised collection and analysis protocols. Evidence suggests that combining multiple biomarkers improves sensitivity and specificity compared with single-marker approaches. Emerging AI and ML tools show significant potential for improving biomarker discovery, integrating multi-omic datasets, and enhancing diagnostic and prognostic accuracy. Conclusions: Liquid biopsy represents a transformative tool for GBM management, with the capacity to overcome limitations of conventional diagnostics and provide real-time insights into tumour biology. By integrating multiple circulating biomarkers and leveraging AI-driven approaches, liquid biopsy could enhance diagnostic precision, enable dynamic disease monitoring, and improve clinical decision-making. However, large-scale validation and standardisation are required before routine clinical adoption can be achieved. Full article

(This article belongs to the Special Issue Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors (2nd Edition))

18 pages, 3619 KB

Open AccessSystematic Review

Safety and Efficacy of Transvaginal Natural Orifice Transluminal Endoscopic (vNOTES) Right Colectomy: A Systematic Review

by Georgia Dimopoulou, Konstantinos Perivoliotis, Evangelos Lolis, Dimitrios Symeonidis, Konstantinos Tepetes and Ioannis Baloyiannis

Cancers 2025, 17(16), 2699; https://doi.org/10.3390/cancers17162699 - 19 Aug 2025

Cited by 1 | Viewed by 412

Abstract

Background/Objectives: We aim to provide pooled data on the safety and efficacy of Transvaginal Natural Orifice Transluminal Endoscopic (vNOTES) right colectomy. Methods: This systematic review was conducted according to the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and [...] Read more.

Background/Objectives: We aim to provide pooled data on the safety and efficacy of Transvaginal Natural Orifice Transluminal Endoscopic (vNOTES) right colectomy. Methods: This systematic review was conducted according to the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary endpoint was the overall complication rate. Quality assessment was based on the NHLBI quality assessment tools. Results: Overall, six studies were included in this review. Overall morbidity rate was 21.9% (95% CI: 10.7–33.2%, p < 0.001), while intraoperative adverse events were noted in 19.9% (p < 0.001) of cases. Mean operation duration was 176.42 (p < 0.001) minutes. Overall hospital stay was 8.68 days (p = 0.002). Conclusions: Our analyses confirm the safety and efficacy of the approach. Given several study limitations, further large-scale and high-quality trials are required. Full article

(This article belongs to the Special Issue Surgical Treatment of Abdominal Tumors)

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16 pages, 3534 KB

Open AccessArticle

Intracellular Targeted Nanocapsules Containing Nanobiotherapeutic Suppress Lung, Liver, Breast and Cervix Cancer Cell Lines by Prodrug Activation or Removal of Intracellular Tyrosine

by ChenHui Zhao and Thomas Ming Swi Chang

Cancers 2025, 17(16), 2698; https://doi.org/10.3390/cancers17162698 - 19 Aug 2025

Viewed by 382

Abstract

Background: Many cancer cell lines, such as Hepa 1-6 (liver), A549 (lung), Hela (cervical), and MCF7 (breast), do not overexpress tyrosinase, an enzyme needed to activate the prodrug quercetin into its active form, o-quinone. In addition, these cancers do not rely on extracellular [...] Read more.

Background: Many cancer cell lines, such as Hepa 1-6 (liver), A549 (lung), Hela (cervical), and MCF7 (breast), do not overexpress tyrosinase, an enzyme needed to activate the prodrug quercetin into its active form, o-quinone. In addition, these cancers do not rely on extracellular tyrosine for growth, as they can produce small amounts intracellularly. Methods: We investigate two therapeutic strategies using nanocapsules containing polyhemoglobin–tyrosinase (PolyHb–Tyr–nano) for action on (1) the intracellular activation of quercetin to o-quinone and (2) the depletion of intracellular tyrosine. We applied these strategies to the four cell lines listed above. Results: (1) PolyHb–Tyr–nano activates quercetin intracellularly, increasing o-quinone levels and reducing cancer cell viability. (2) PolyHb–Tyr–nano alone suppresses tumor growth by lowering intracellular tyrosine. Furthermore, PolyHb–Tyr–nano shows selective cytotoxicity, with an LD₅₀ of 0.7808 mg/mL in Hepa 1-6, compared with an extrapolated LD₅₀ of 84,181 mg/mL in the normal liver cells. In contrast, quercetin activation results in an LD₅₀ of 2.73 mg/mL in Hepa 1-6 and 74.18 mg/mL in normal hepatocytes. Conclusions: PolyHb–Tyr–nano offers dual therapeutic functions: (1) quercetin prodrug activation and (2) intracellular tyrosine depletion. Full article

(This article belongs to the Special Issue Nano-Targeting of Cancer)

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15 pages, 1300 KB

Open AccessArticle

Optimizing Motion Management and Baseline Shifts in Magnetic Resonance-Guided Spine Stereotactic Body Radiation Therapy

by Yao Ding, Travis C. Salzillo, Debra N. Yeboa, Martin C. Tom, Zhiheng Wang, Parmeswaran Diagaradjane, Ergys Subashi, Jinzhong Yang, Todd Swanson, Thomas Beckham, Chenyang Wang, Amol J. Ghia, Tina Briere, Jihong Wang, Fabienne Lathuilière, Sneha Cloake and Eun Young Han

Cancers 2025, 17(16), 2697; https://doi.org/10.3390/cancers17162697 - 19 Aug 2025

Viewed by 455

Abstract

Background: Stereotactic body radiation therapy (SBRT) has proven effective in controlling spinal lesions with minimal toxicity, primarily due to its ability to limit spinal cord dose. Recent advances in MR-linac (MRL) technology offer superior spinal cord visualization and real-time gating, which can facilitate [...] Read more.

Background: Stereotactic body radiation therapy (SBRT) has proven effective in controlling spinal lesions with minimal toxicity, primarily due to its ability to limit spinal cord dose. Recent advances in MR-linac (MRL) technology offer superior spinal cord visualization and real-time gating, which can facilitate dose escalation in spinal tumor treatment while maintaining safety. Purpose: This study aimed to optimize motion management for spine SBRT on an MRL by analyzing patient-specific motion dynamics and evaluating the most effective registration structures. We hypothesized that baseline shifts (BLS) would improve delivery efficiency while maintaining spinal cord dose constraints. The goal was to establish displacement thresholds and assess the role of baseline shift correction adaptative planning in improving treatment delivery efficiency. Methods: Twelve patients underwent two MRI sessions on the MRL. The optimal registration structure was identified, and intrafraction motion was assessed to calculate delivery efficiency. Baseline shift (BLS) simulations were applied for five cases that showed significant motion and suboptimal delivery efficiency, and the dosimetric impact of the BLS was evaluated. The simulated BLS-based plan adaptation was implemented via a segment aperture morphing adapt-to-position workflow. Results: The most stable registration structure was the spinal canal plus three adjacent vertebrae. Cine imaging revealed average intrafraction motion (95th to 5th percentiles) of 0.8 ± 0.5 mm in the right-left (RL) direction, 0.9 ± 0.6 mm in the anterior–posterior (AP) direction, and 0.7 ± 0.5 mm in the SI direction. Simulated BLS improved delivery efficiency to >80% in all but one case, with a ±1 mm displacement threshold tolerance. While target coverage remained consistent after BLS simulation, the spinal cord dose increased by 7–60%, exceeding the 14 Gy constraint in three of the five simulated cases. Conclusions: Cine imaging and BLS can enhance delivery efficiency in spine SBRT but may increase spinal cord dose. These findings underscore the need for careful patient selection, advanced motion management, and patient-specific BLS protocols. Full article

(This article belongs to the Special Issue Stereotactic Body Radiation and Stereotactic Ablative Radiotherapy Therapy for Cancers 2nd edition)

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17 pages, 676 KB

Open AccessReview

Understanding Contemporary Endometrial Cancer Survivorship Issues: Umbrella Review and Healthcare Professional Survey

by Tracey DiSipio, Jemma Turner, William Da Silva, Elizabeth Driscoll, Marta Preston, Krystel Tran, Nicla Varnier-Lui, Hui-Ling Yeoh, Dayajyot Kaur, Kathryn Alsop, Sandra C. Hayes, Monika Janda and Rosalind R. Spence

Cancers 2025, 17(16), 2696; https://doi.org/10.3390/cancers17162696 - 19 Aug 2025

Viewed by 535

Abstract

Background/Objectives: Advances in endometrial cancer treatment, such as minimally invasive surgery and the introduction of targeted therapies, could influence survivorship and result in changes in issues experienced by survivors of endometrial cancer. To improve endometrial cancer survivorship, it is first necessary to [...] Read more.

Background/Objectives: Advances in endometrial cancer treatment, such as minimally invasive surgery and the introduction of targeted therapies, could influence survivorship and result in changes in issues experienced by survivors of endometrial cancer. To improve endometrial cancer survivorship, it is first necessary to understand it. Therefore, the purpose of this study was to describe contemporary endometrial cancer survivorship issues. Methods: This study involved an umbrella review and cross-sectional survey of healthcare professionals. The umbrella review involved searching Medline (2013–2023) to identify published reviews describing survivorship outcomes in endometrial cancer survivors. Articles were screened and survivorship outcomes were extracted. Healthcare professionals working with patients diagnosed with endometrial cancer were asked to (1) rate the relevance of each survivorship outcome identified in the review, and (2) list any additional issues considered of clinical relevance. Results: Following the screening of 201 articles (159 papers excluded: n = 1 duplicate; n = 158 ineligible), 42 review articles were included and 25 survivorship outcomes identified including physical health (e.g., fatigue, pain), fertility (e.g., parity), quality of life (e.g., cognitive wellbeing), treatment-related toxicities, and mental health outcomes (e.g., anxiety). The cross-sectional survey was completed by 37 healthcare professionals (two-thirds being medical oncologists or gynaecological oncologists) working across Australia and New Zealand, with outcomes rated as relevant by 30% (for cachexia) to 100% (for body weight/obesity and functional wellbeing of respondents. An additional 28 survivorship issues not identified in the review were reported by healthcare professionals. Conclusions: The current endometrial cancer survivorship literature is limited. The review, together with expert input from healthcare professionals, identified 53 survivorship issues. These findings will now inform development of a survey to explore the frequency, impact, and severity of survivorship issues from the perspective of endometrial cancer survivors, the results of which will guide the provision of supportive cancer care, in addition to guiding research and clinical practice. Full article

(This article belongs to the Special Issue Empowering Cancer Survivors: A Comprehensive Approach to Supportive Care Through Pharmacological and Non-Pharmacological Approaches Including Exercise, Physical Activity and Nutrition)

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25 pages, 5512 KB

Open AccessArticle

Unraveling the Clinical Landscape of RNA Modification Regulators with Multi-Omics Insights in Pan-Cancer

by Qingman Li, Jingjing Zhang, Zuyi Cao, Jiale Wang, Jiaxing Song and Xianfu Yi

Cancers 2025, 17(16), 2695; https://doi.org/10.3390/cancers17162695 - 19 Aug 2025

Viewed by 483

Abstract

Background/Objectives: Cancer remains a major global health challenge, with RNA modifications increasingly recognized as key regulators of tumor progression. However, integrated pan-cancer analyses across multiple modification types are limited. Methods: We performed a comprehensive analysis of 170 RNA modification-related genes across 33 cancer [...] Read more.

Background/Objectives: Cancer remains a major global health challenge, with RNA modifications increasingly recognized as key regulators of tumor progression. However, integrated pan-cancer analyses across multiple modification types are limited. Methods: We performed a comprehensive analysis of 170 RNA modification-related genes across 33 cancer types, uncovering diverse expression, mutation, and epigenetic patterns. Results: Key regulators such as IGF2BP3, CFI, and ELF3 showed cancer-specific prognostic significance. We developed an RNA Modification Score (RMS) with strong prognostic performance (AUC up to 0.92), correlating with the tumor stage, immune infiltration, and immunotherapy response. High-risk groups exhibited immune checkpoint dysregulation and enriched M1 macrophages in glioblastoma. Drug screening highlighted oncrasin-72 as a potential therapy. Validation via single-cell/spatial transcriptomics and immunohistochemistry confirmed the spatial localization of critical genes like CFI and ELF3. Conclusions: Our study reveals the multifaceted role of RNA modifications in cancer, providing a translational framework for personalized prognosis and therapy in precision oncology. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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21 pages, 4602 KB

Open AccessReview

Spatially Encoded Oncogenesis and Transcriptional Plasticity in Meningioma: Drivers of Therapeutic Resistance and Opportunities for Targeted Intervention

by Matthew A. Abikenari, Amit Regev, Brandon H. Bergsneider, Vratko Himic, Shreyas Annagiri, Lily H. Kim, Ravi Medikonda, John Choi, Sanjeeva Jeyaretna, Daniel M. Fountain and Michael Lim

Cancers 2025, 17(16), 2694; https://doi.org/10.3390/cancers17162694 - 19 Aug 2025

Viewed by 632

Abstract

Whilst typically benign, a subset of meningiomas displays aggressive and recurrent behavior. There is a paucity of reliable treatment options for this subset of patients and a relative lack of consensus on how to best manage these patients. This clinical challenge reflects underlying [...] Read more.

Whilst typically benign, a subset of meningiomas displays aggressive and recurrent behavior. There is a paucity of reliable treatment options for this subset of patients and a relative lack of consensus on how to best manage these patients. This clinical challenge reflects underlying molecular complexity, driven by NF2, TRAF7, and CDKN2A/B mutations alongside pervasive epigenetic dysregulation. High-throughput molecular profiling studies have proposed biologically distinct meningioma subgroups with varying clinical trajectories and therapeutic vulnerabilities. Distinct cell lineages of meningeal precursors are now appreciated to be essential in the establishment of the meninges. The numerous cellular lineages involved in meningeal development, the heterogeneity of meningioma location and (epi)genomic behavior, and the variability in its clinical and radiological manifestations raise the question of what critical insights can be gained by understanding meningeal development during embryogenesis to understand meningioma tumorigenicity. The current paper examines this paradigm by highlighting spatially linked mechanisms of anaplasia and treatment resistance, including the role of neural crest-derived convexity meninges in promoting dedifferentiation via YAP/TAZ signaling and mesoderm-derived skull base regions in maintaining TRAF7-mediated vulnerabilities. We further elucidate the emerging synthetic lethal paradigms, CRISPR-enabled target discovery, and PROTAC-mediated degradation strategies that may transform the therapeutic landscape of clinically challenging meningiomas driven by complex oncogenic circuitry. By bridging embryogenesis, spatial genomics, and molecular targeting, we propose a developmentally informed, lineage-stratified model for advancing precision therapeutics in high-grade and recurrent meningiomas. Full article

(This article belongs to the Special Issue Neuroscience of Brain Tumors)

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16 pages, 3156 KB

Open AccessArticle

Tumor-Specific EphA2 Receptor Tyrosine Kinase Inhibits Anti-Tumor Immunity by Recruiting Suppressive Myeloid Populations in Murine Models of Non-Small Cell Lung Cancer

by Eileen Shiuan, Shan Wang and Dana M. Brantley-Sieders

Cancers 2025, 17(16), 2693; https://doi.org/10.3390/cancers17162693 - 19 Aug 2025

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Abstract

Background: EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and [...] Read more.

Background: EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment. Methods: Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in murine models of non-small cell lung cancer (NSCLC). Results: Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrates via flow cytometry revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T-cell activation, particularly in CD8+ T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1 in RNA expression analyses. Conclusions: Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit the activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape. Full article

(This article belongs to the Section Molecular Cancer Biology)

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18 pages, 1447 KB

Open AccessArticle

Spontaneous Mesotheliomas in Germline Bap1 Heterozygous Mice from Different Genetic Backgrounds

by Yuwaraj Kadariya, Li Zhang, Eleonora Sementino, Eric Ross and Joseph R. Testa

Cancers 2025, 17(16), 2692; https://doi.org/10.3390/cancers17162692 - 19 Aug 2025

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Abstract

Background: BAP1 mutation carriers are predisposed to the development of mesothelioma. In mice, there is limited data and controversy about whether germline Bap1 heterozygous mutations alone cause mesothelioma. However, a marked increase in mesothelioma incidence is observed in Bap1-mutant mice upon even [...] Read more.

Background: BAP1 mutation carriers are predisposed to the development of mesothelioma. In mice, there is limited data and controversy about whether germline Bap1 heterozygous mutations alone cause mesothelioma. However, a marked increase in mesothelioma incidence is observed in Bap1-mutant mice upon even minimal asbestos exposures. Methods: To address this issue, we investigated spontaneous mesothelioma development over the lifetime of a large cohort of Bap1-mutant and wild-type (WT) mice across several genetic backgrounds. To determine if the incidence of mesotheliomas in Bap1-mutant mice is significantly increased compared to WT mice, we performed statistical analyses using frequentist and Bayesian frameworks. In the Bayesian framework, to model the probability of disease occurrence, a non-informative prior was used for Bap1-mutant mice, whereas an informative prior for the WT group was derived from historical data spanning the animals’ lifetimes. Multiple strategies were employed to incorporate historical data and infer the informative prior, including a meta-analysis, assuming a consistent probability of mesothelioma across historical datasets, and applying Bayesian meta-analytic predictive priors derived from historical data. Posterior distribution was used, and a comparison was made using odds ratio, risk difference, and risk ratio. Results: Spontaneous mesotheliomas were detected in 2/329 Bap1-mutant and 0/227 WT mice from various genetic backgrounds. Using four statistical approaches, the results did not detect a significant difference in the probabilities of mesothelioma occurrence between Bap1-mutant and WT mice. Conclusions: Based on these analyses, we cannot conclude that germline Bap1-mutant mice have a significantly increased risk of mesothelioma in the absence of asbestos exposure. Full article

(This article belongs to the Special Issue Mesothelioma—from Diagnosis to Treatment)

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13 pages, 1524 KB

Open AccessArticle

A Comparison of the Flow Cytometric Analysis Results of Benign and Malignant Serous Tumors of the Ovary

by Ozgur Ozdemir, Mustafa Emre Duygulu, Yavuz Tekelioglu, Safak Ersoz and Suleyman Guven

Cancers 2025, 17(16), 2691; https://doi.org/10.3390/cancers17162691 - 19 Aug 2025

Viewed by 372

Abstract

Background/Objectives: Flow cytometric analysis of cellular DNA content has prognostic importance in ovarian cancer and its measurement could contribute to clinical practice. The aim of this study was to compare serous cystadenoma and serous cystadenocarcinoma cases in terms of their flow cytometric [...] Read more.

Background/Objectives: Flow cytometric analysis of cellular DNA content has prognostic importance in ovarian cancer and its measurement could contribute to clinical practice. The aim of this study was to compare serous cystadenoma and serous cystadenocarcinoma cases in terms of their flow cytometric analysis results. Methods: In total, 60 serous ovarian tumor cases (30 cases of ovarian serous cyst adenoma and 30 cases of ovarian serous cystadenocarcinoma) in paraffin blocks were extracted from hospital pathology archives for flow cytometric analysis. Cell cycle changes, aneuploidy ratio, and annexin V levels were compared. Results: The S phase cell ratio, proliferative index, aneuploidy cell ratio, and annexin V apoptotic index were significantly higher in the cancer group compared to the cystadenoma group. However, the G2/M phase cell ratio was found to be similar in both groups. When the annexin V apoptotic index cutoff value was selected as 27.65%, the sensitivity was calculated as 90.0% and the specificity as 93.3% for predicting serous ovarian carcinoma (AUC, 0.872; p < 0.001; 95% CI, 0.761–0.984). Conclusions: In serous cystadenocarcinoma cases, cell cycle activity was increased compared to serous cyst adenoma, but the similarity of G2/M activities suggested that serous cystadenocarcinoma may be a member of the “metaneoplasia” process. The detection of annexin V expression in ovarian tumors by flow cytometric analysis is a cheap, fast, and easy diagnostic method that can be used in the diagnosis of ovarian cancer. Annexin V expression is an effective biomarker with high sensitivity and specificity that could be used in the diagnosis of serous ovarian cancer. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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Cancers, Volume 17, Issue 16 (August-2 2025) – 121 articles

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